Chapter 22: Delirium, Dementia, and Rapidly Progressive Dementia

When assessing patients with acute or chronic changes in cognition, two interrelated questions should be pursued during the history and examination:

• Is the presentation focal or global?

• Is the problem arising from primary brain pathology or a systemic process that is affecting the brain?

Focal deficits suggest focal brain pathology (e.g., stroke, tumor, abscess), although focal findings can occur with systemic disease in the absence of focal central nervous system pathology (e.g., focal seizures or hemichorea caused by hyperglycemia or aphasia caused by cefepime toxicity). Global dysfunction is generally due to systemic pathology affecting the brain, although diffuse intrinsic brain pathology can also cause a global encephalopathy (e.g., multiple strokes, multiple metastases, a diffuse infiltrating malignant lesion, acute disseminated encephalomyelitis).

Focal cognitive deficits may give the initial misleading impression that there is a global encephalopathy. Examples of focal deficits that can initially appear to be global encephalopathic states unless examined in detail include Wernicke’s aphasia producing lack of comprehension and abnormal speech, and transient global amnesia causing isolated short-term memory impairment. On the other hand, global cognitive dysfunction may make it challenging to elicit coexisting focal deficits on examination since a core feature of global cognitive dysfunction is inattention, which can make it difficult to examine cognitive functions that rely on attention such as language, memory, and ability to follow commands.

Delirium refers to acute altered mental status (developing over hours to days), and dementia refers to chronic development of cognitive dysfunction (over years). Rapidly progressive dementia describes subacute development of cognitive dysfunction (over weeks to months).

Delirium is characterized by acute onset of altered mental status with fluctuations in both symptoms and level of arousal. Delirium causes a global encephalopathy, with inattention as the core feature. The differential diagnosis for acutely altered mental status is as broad as the differential diagnosis for any condition in medicine. Delirium can be caused by intrinsic brain pathology (see “Neurologic Causes of Acutely Altered Mental Status” below), systemic disease affecting the brain (e.g., renal or hepatic failure, systemic infections, electrolyte disturbances, hypoglycemia or hyperglycemia, hyperammonemia, hypothyroidism or hyperthyroidism), medications, toxins, drugs, or drug withdrawal. Primary psychiatric etiologies may also be causative or contributory. Although new changes in cognition or personality in patients with psychiatric disease may be due to the underlying psychiatric disease, potential reversible medical causes should be sought.

Patients who are elderly or have baseline neurologic dysfunction (e.g., dementia) are at increased risk of delirium due to any of the above etiologies (as well as due to the disorienting environment of the hospital if the patient is hospitalized).

Neurologic Causes of Acutely Altered Mental Status

Neurologic etiologies of acute-onset altered mental status include seizures, stroke and cerebrovascular disease, CNS infections, and transient global amnesia.

Seizures as a Cause of Acutely Altered Mental Status

Nonconvulsive seizures can cause alterations in cognition and level of consciousness ranging from encephalopathy to coma. Diagnosis of nonconvulsive seizures may require continuous EEG monitoring (see “Nonconvulsive Status Epilepticus” in Ch. 18). A postictal state following a seizure can also lead to changes in mental status ranging from confusion to coma. An unwitnessed seizure with subsequent postictal state should be considered as a potential etiology of altered mental status, especially in patients who improve spontaneously from their altered state without any specific medical intervention.

Stroke and Cerebrovascular Disease as Causes of Acutely Altered Mental Status

Although stroke as a cause of acute alteration in mental status is generally easily recognized when focal features are present, certain regions of infarction may lead to global cognitive dysfunction without obvious focal signs. Additionally, focal signs such as subtle visual field deficits or neglect may be hard to elicit in confused patients. Sites of infarction that can lead to changes in mental status without obvious focal features include the thalamus (especially bilateral thalamic strokes due to artery of Percheron territory infarct; see “Posterior Cerebral Artery Territory Infarction” in Ch. 7), inferior division of the right middle cerebral artery (MCA), anterior cerebral artery (ACA) territory (if motor fibers to the leg are spared), anterior or complete posterior cerebral artery (PCA) territory (affecting the hippocampus/medial temporal lobe), and diffuse emboli.

Subacute development of a subdural hematoma can lead to subacute development of altered mental status (see “Subdural Hematoma” in Ch. 19).

CNS Infections as a Cause of Acutely Altered Mental Status

Fever and altered mental status should raise concern for meningitis, encephalitis, or intracranial abscess (see Ch. 20). Although a systemic infection can cause alteration in mental status without direct CNS involvement, lumbar puncture should be considered in patients with fever and altered mental status if there is no obvious systemic source of infection.

Transient Global Amnesia

Transient global amnesia (TGA) is a discrete episode (usually lasting 12 hours or less) during which the ability to form new memories is lost (anterograde amnesia). This inability to form new memories leads to repetitive questioning (“Where am I?”, “How did I get here?”) since the short-term memory buffer is essentially erased every few minutes. Patients with TGA may be disoriented with respect to time and place and forget events of the preceding day(s) but do not forget their name or other personal information. If personal information is forgotten, this is highly suggestive of a psychogenic etiology of amnesia (e.g., fugue state) rather than a neurologic etiology.

A trigger commonly precedes TGA such as an emotionally intense situation (e.g., stressful event, sexual intercourse), vigorous exercise, or exposure to cold water. TGA is often idiopathic, but may be the presentation of a medial temporal lobe infarct (PCA territory), and so neuroimaging should be performed. In some patients with TGA, a punctate region of diffusion restriction can be seen in the hippocampus (Fig. 22–1), leading some to hypothesize that all TGA is a vascular phenomenon, although the pathophysiology of the condition is unknown. Although seizures can produce ictal or postictal amnesia, the period of amnesia with seizures is generally shorter than that in TGA, and seizures are often recurrent, whereas TGA usually lasts for hours and only very rarely recurs.

Medical Causes of Acutely Altered Mental Status

“Toxic-Metabolic” Etiologies of Altered Mental Status

“Toxic-metabolic” encephalopathy refers to altered mental status due to medications, toxins, and/or metabolic abnormalities (e.g., uremia, hepatic failure). When faced with a case of potential toxic-metabolic encephalopathy, the consultant neurologist should try to determine which “toxic” and/or “metabolic” factor(s) may account for the patient’s altered state: Does the degree of renal or hepatic failure differ significantly from the patient’s baseline? Has a potentially deliriogenic medication been recently added? Has an old medication changed in dose or could it be reaching toxic levels at its previously tolerated dose due to new renal or hepatic dysfunction? Applying the catch-all “toxic-metabolic” term to encephalopathies without careful consideration can lead to premature closure and missed diagnoses. By thinking critically through any and all potential neurologic and systemic etiologies of altered mental status, reversible etiologies may be uncovered.

An important example of this is the case of medications. Nearly any medication can cause altered mental status. Neurologists are in the unique position of having seen and diagnosed cases of medication-induced neurotoxicity from medications that only rarely cause neurotoxicity. Other practitioners may have used a medication countless times without seeing neurologic side effects, and thus may not associate a particular drug with the potential to cause delirium. For example, many commonly used antibiotics can rarely cause encephalopathy, including cephalosporins (in particular cefepime and ceftazidime), fluoroquinolones, macrolides, metronidazole, and isoniazid (Bhattacharyya et al., 2016). Cephalosporin-associated encephalopathy is often associated with nonconvulsive seizures, fluoroquinolone- and macrolide-associated encephalopathy with hallucinations and psychotic symptoms, and metronidazole-associated encephalopathy with ataxia and characteristic MRI findings in the cerebellar white matter. Patients who develop alterations in mental status of unclear etiology on any of these medications should generally have these medications replaced with alternative antibiotics given the possibility of antibiotic-associated encephalopathy.

Wernicke’s Encephalopathy

Wernicke’s encephalopathy is characterized by the triad of encephalopathy, ataxia, and eye movement abnormalities (nystagmus and/or gaze palsies), and is caused by thiamine (vitamin B1) deficiency that occurs in the setting of malnutrition (e.g., in patients with alcoholism, anorexia, gastric bypass surgery, or hyperemesis gravidarum). In many cases of Wernicke’s encephalopathy, the complete triad is not present, requiring a high index of suspicion for the condition. Wernicke’s encephalopathy can be precipitated acutely by giving glucose to a thiamine-deficient patient without giving thiamine simultaneously. Therefore, thiamine should always be given with glucose infusions in the setting of acutely altered mental status to prevent this complication in patients whose history may be unknown. Serum thiamine levels take a long time to return and may be unreliable, so empiric treatment with intravenous thiamine should be provided if there is any concern for Wernicke’s encephalopathy. MRI in Wernicke’s encephalopathy can demonstrate signal abnormalities in the mammillary bodies, thalamus, and around the third and fourth ventricles (Fig. 22–2).

Not treating Wernicke’s encephalopathy can result in Korsakoff’s syndrome, characterized by anterograde amnesia and confabulation.

If the cause of acute altered mental status is unclear after careful review of the patient’s medications and active medical issues, EEG should be considered to look for non-convulsive seizures, brain imaging should be considered to look for a causative lesion, and lumbar puncture should be considered (if there is concern for CNS infection or inflammation).

Dementia is defined as cognitive decline in one or more domains (e.g., memory, language, attention, visuospatial processing, social behavior) sufficient to impair independent daily function.

Causes of Dementia

Insidious onset and gradual progression of cognitive impairment over months to years may be secondary to neurodegenerative diseases (Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia being the most common), chronic cerebrovascular disease (vascular dementia), or due to potentially treatable causes such as:

• Systemic diseases:

  • Metabolic deficiency: vitamin B12 deficiency

  • Endocrine disease: Hypothyroidism

  • Chronic infection: AIDS, syphilis

  • Obstructive sleep apnea

• Medications, such as psychotropic medications in older adults

• Toxins, such as alcohol or drug abuse, heavy metal poisoning

• Intracranial pathology, such as tumor, chronic subdural hematoma, normal pressure hydrocephalus

• Psychiatric disease, such as depression

Neurodegenerative disease is progressive with no disease-modifying medications, and treatment is limited to symptomatic management and supportive care. Therefore, part of the initial evaluation of patients with dementia is to assess for potentially treatable causes. The history should evaluate for depression, medication history, and sleep apnea. Examination should assess for focal findings that might suggest focal underlying pathology. Mental status testing should be performed to assess for the type and extent of impairment(s), for example with the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MOCA).

Frontal release signs may be present on physical examination in patients with dementia, but are not universally present and some of these signs can be seen in non-demented elderly patients (and occur normally in infants as does Babinski’s sign). Frontal release signs include:

• Snout reflex: the patient purses the lips when the examiner taps at the center of the lips.

• Grasp reflex: the patient cannot inhibit grasping the examiner’s hand or an object when placed into the patient’s hand.

• Suck reflex: the patient will attempt to suck any object (such as a pen) moved toward the mouth.

• Rooting reflex: lightly touching the patient’s cheek causes the patient to turn the head toward that side.

• Palmomental reflex: briskly scratching the patient’s palm causes a twitch of the ipsilateral chin.

Laboratory evaluation for dementia should include vitamin B12, thyroid-stimulating hormone (TSH), and neuroimaging (ideally MRI). HIV and syphilis testing should be considered in patients with risk factors for these diseases. Neuroimaging may reveal an etiology of altered cognition such as malignancy (primary or metastatic), subdural hematoma, normal pressure hydrocephalus, or a characteristic pattern of atrophy associated with a particular neurodegenerative etiology. Formal neuropsychological testing can help to better characterize the nature and degree of cognitive impairment, which may be helpful both in making a diagnosis and in guiding cognitive therapy.

The core features of the most common dementia syndromes are presented in Table 22–1. Multiple underlying pathologies frequently coexist (e.g., Alzheimer’s disease and vascular dementia). Some ask why it is important to distinguish between types of dementia clinically/radiologically when there are currently no specific disease-modifying therapies. A precise diagnosis allows for tailoring of symptomatic therapy and also aids in discussion of prognosis. In addition, clinical-radiologic diagnosis is essential to characterizing these diseases in order to improve early identification toward the goal of developing disease-modifying therapies.

Mild Cognitive Impairment

Mild cognitive impairment (MCI) refers to cognitive decline with preserved ability to function independently. Patients with MCI often present for evaluation due to awareness of their deficits, whereas patients with dementia are commonly brought for evaluation by family members and may be less aware of their deficits. MCI is estimated to have a risk of progression to dementia of approximately 10% per year. The most common form of MCI is amnestic MCI in which the patient has isolated memory loss, although patients may have deficits in another individual cognitive domain or multiple domains. In patients with MCI, there does not appear to be a clear benefit to using the cholinesterase inhibitors used in patients with Alzheimer’s disease (see “Treatment of Alzheimer’s Disease” below), although some practitioners will consider their use in patients in whom MCI is thought likely to be due to underlying Alzheimer’s pathology.

Alzheimer’s Disease

Clinical Features of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative cause of dementia. In most cases, the first and most prominent cognitive deficit is in memory, specifically memory for recent events (episodic memory). Patients may forget to do things they had planned to do (e.g., miss appointments), forget having done something, or forget a conversation. Other symptoms that may also be present initially or may emerge as the disease progresses include getting lost, decreased performance at work, and word-finding difficulties. The disease progresses inexorably toward a state of global dementia with patients generally losing an average of 3 points per year on the MMSE.

Most cases of AD are sporadic, although some are familial. Familial cases of AD usually begin at a younger age than sporadic cases. Inheritance of familial AD is autosomal dominant due to mutations in the amyloid precursor protein (APP), presenilin 1, or presenilin 2 genes that lead to overproduction of amyloid. Risk of development of Alzheimer’s disease is increased in patients with the ε4 allele of apolipoprotein E (APOE). Patients with Down’s syndrome also develop early AD since amyloid precursor protein is found on chromosome 21, and so it is present in triplicate in patients with trisomy 21.

Posterior cortical atrophy—In posterior cortical atrophy (also called the visual variant of AD), neurodegeneration occurs specifically in parieto-occipital regions, leading to visual cognitive deficits (e.g., elements of Balint syndrome; see “Balint syndrome” in Ch. 6). The underlying pathology is most commonly Alzheimer pathology, although posterior cortical atrophy can also be caused by other types of neurodegenerative pathology.

Neuroimaging and Laboratory Features of Alzheimer’s Disease

MRI in AD usually demonstrates bilateral atrophy in medial temporal regions (hippocampus and entorhinal cortex) and the superior parietal lobe (Fig. 22–3). Nuclear medicine studies in AD show hypometabolism on positron emission tomography (PET) and reduced perfusion on single photon emission computed tomography (SPECT) in bilateral temporoparietal cortex, posterior cingulate cortex, and precuneus. Amyloid PET imaging to identify amyloid burden in the brain is currently mostly used in research settings (e.g., to determine eligibility for clinical trials).

In the cerebrospinal fluid (CSF), low Aβ42 and increased tau (leading to decreased Aβ42/tau ratio) can predict underlying Alzheimer pathology in the appropriate clinical setting. Amyloid is presumably low in the CSF because it has accumulated in plaques in the brain.

Treatment of Alzheimer’s Disease

Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the N-methyl-d-aspartate (NMDA) antagonist memantine may provide modest symptomatic benefit in cognition in patients with AD. Gastrointestinal side effects can occur with the cholinesterase inhibitors. A common treatment strategy in patients with AD is to use a cholinesterase inhibitor initially (if tolerated), and to add memantine as patients progress to moderate/severe dementia. Otherwise, care of patients with AD is supportive.

Dementia With Lewy Bodies

Clinical Features of Dementia With Lewy Bodies

Dementia with Lewy bodies (DLB) is one of the Parkinson-plus syndromes along with multiple systems atrophy, progressive supranuclear palsy, and corticobasal degeneration (see Ch. 23). These are all diseases in which there are parkinsonian symptoms along with other types of neurologic dysfunction. In addition to a dementia characterized by initial deficits in visuospatial and executive function, patients with DLB develop parkinsonism, visual hallucinations (usually nonthreatening hallucinations of people or animals), and fluctuations in attention and level of arousal. History of rapid eye movement (REM) sleep behavior disorder is common (as in other synucleinopathies; see “Nonmotor Aspects of Parkinson’s Disease” in Ch. 23), and neuroleptic sensitivity (worsened parkinsonism and/or cognition with administration of neuroleptics) and autonomic dysfunction (orthostasis, constipation, incontinence, sexual dysfunction) are frequently present.

Patients with Parkinson’s disease (see “Parkinson’s Disease” in Ch. 23) can develop dementia over the course of the disease. DLB is generally distinguished from Parkinson’s disease dementia by the following clinical features: patients with DLB develop symptoms and signs of dementia before or simultaneously with features of parkinsonism (in Parkinson’s disease dementia, parkinsonism usually precedes dementia by years), parkinsonism in DLB is usually symmetric (in Parkinson’s disease, parkinsonism usually begins asymmetrically), parkinsonism in DLB is usually less responsive to levodopa (or may not respond at all) compared to patients with Parkinson’s disease (whose parkinsonism generally responds to levodopa).

Neuroimaging Features of Dementia With Lewy Bodies

There is no characteristic pattern of atrophy on structural imaging in DLB, but nuclear imaging may show hypometabolism/hypoperfusion in occipital and temporoparietal regions (compared to just temporoparietal hypometabolism/hypoperfusion in AD).

Treatment of Dementia With Lewy Bodies

As in AD, cholinesterase inhibitors and memantine may be useful in symptomatic management of cognitive dysfunction in DLB. As in the other Parkinson-plus syndromes, there is usually little or no response to dopaminergic therapies (in contrast to Parkinson’s disease), but if parkinsonism is a prominent disabling feature in a patient with DLB, a trial of levodopa can be considered. Symptomatic treatment can be considered for mood, REM sleep behavior disorder (clonazepam), and autonomic dysfunction.

Frontotemporal Dementia

Frontotemporal dementia (FTD) includes two categories of dementia syndromes: behavioral variant FTD (bvFTD) and primary progressive aphasia (PPA). As the names suggest, bvFTD is characterized by personality changes and neuropsychiatric dysfunction, and PPA is characterized by language deficits. Behavioral and personality changes in bvFTD can include anything from apathy to disinhibition, and from social withdrawal to socially deviant behavior. Patients generally lack insight into the changes in their personality and behavior. Other common features include loss of empathy, obsessive compulsive or perseverative behaviors, and executive dysfunction. PPA has three variants with particular language deficits: nonfluent/agrammatic, semantic, and logopenic (Table 22–2). Neuroimaging in FTD shows selective frontotemporal atrophy (Fig. 22-4) that may be very focal within language areas in PPA.

The most common underlying pathologic findings in FTD are tau or TDP-43, although AD pathology is the most common underlying pathology in the logopenic variant of PPA. Some patients develop syndromes of overlap of FTD with motor neuron disease, corticobasal degeneration, or progressive supranuclear palsy. Treatment is symptomatic/supportive. Selective serotonin reuptake inhibitors (SSRIs) may be helpful in managing the psychiatric symptoms of bvFTD. Unlike patients with AD or DLB, patients with FTD do not appear to benefit from cholinesterase inhibitors.

Vascular Dementia

Vascular dementia refers to impaired cognitive function due to cerebral infarction. This may be due to accumulation of cognitive deficits from serial strokes in a stepwise manner, more insidious with chronic accumulation of subcortical microvascular disease, or some combination of the two. Clinical signs depend upon site(s) of prior infarction, but executive dysfunction and cognitive slowing are common, and focal features, upper motor neuron signs, and/or pseudobulbar affect may be present. In cases of insidious cognitive decline and evidence of both atrophy and subcortical white matter disease on neuroimaging, the differentiation between AD, vascular dementia, and overlap of the two may not be possible. There may be some benefit of cholinesterase inhibitors and memantine in vascular dementia as in AD, so a medication trial may be attempted in ambiguous or presumed overlap cases. Secondary stroke prevention is of course important as in any patient with prior stroke (see “Secondary Prevention of Ischemic Stroke” in Ch. 19).

Normal Pressure Hydrocephalus

Although not a neurodegenerative disease, normal pressure hydrocephalus (NPH) is discussed here since it should be considered in the differential diagnosis of patients presenting with dementia. The predominant symptoms of NPH are gait dysfunction, urinary incontinence, and dementia. In this condition, ventricular enlargement leads to frontal lobe dysfunction, and CSF diversion by ventriculoperitoneal (VP) shunt can lead to improvement. NPH may be idiopathic or can be caused by impaired CSF circulation caused by prior subarachnoid hemorrhage or meningitis.

In most patients with NPH, gait dysfunction is the first sign of the disorder, and dementia and urinary incontinence emerge later in the course of the condition. The classic gait pattern in NPH is wide based and “magnetic”: the feet appear to be magnetically drawn back to the floor as soon as they are lifted. (Note that severe proprioceptive dysfunction due to large-fiber neuropathy, sensory ganglionopathy, or posterior column dysfunction can also cause a magnetic gait). The walking problem in NPH is due to dysfunction of higher order control of gait, and is not due to weakness or incoordination. This can be demonstrated by having the patient bicycle the legs in bed. Bicycling movements require strength and coordination and are usually normal in NPH in marked contrast to the very impaired gait.

The diagnosis of NPH is suggested by the clinical picture in conjunction with radiologic evidence of ventriculomegaly out of proportion to cerebral atrophy. With aging and/or dementia, there is cerebral atrophy and subsequent ex vacuo dilatation of the ventricles to fill the remaining space. This must be distinguished from ventricular enlargement due to hydrocephalus. One way to quantify ventriculomegaly is to calculate the Evans ratio, calculated by measurements on axial neuroimaging. The Evans ratio is calculated by dividing the largest “wingspan” of the frontal horns of the lateral ventricles by the maximum horizontal width between the left and right inner table of the skull on the same axial slice. An Evans ratio >0.31 is considered to be consistent with NPH in the appropriate clinical context (Fig. 22–5).

Diagnosis of NPH is made by noting improvement of gait and/or cognitive function after a large-volume lumbar puncture or continuous lumbar drainage of spinal fluid. Improvement with one of these tests suggests a likely response to placement of a VP shunt, although even some patients who do not improve with lumbar puncture or lumbar drain may still improve with a VP shunt. This leads to challenging clinical decision making since the differential diagnosis may be between AD with no disease-modifying treatment and the possibility of NPH that could respond to VP shunt (but with the inherent risks of complications of shunt placement; see “Ventriculoperitoneal Shunt” in Ch. 25). In NPH, gait dysfunction is generally more likely to improve with a VP shunt than cognitive impairment.

Dementia usually arises gradually and is ongoing for months to years by the time patients present for evaluation. When onset and evolution of dementia are more rapid, the condition is referred to as rapidly progressive dementia. Creutzfeldt-Jakob disease is the quintessential rapidly progressive dementia, but the differential diagnosis for this condition is broad and includes many treatable etiologies (Geschwind et al., 2008; Chitravas et al., 2011):

• Inflammatory conditions:

  • Antibody-mediated/paraneoplastic limbic encephalitis (see “Autoimmune Limbic Encephalitis” in Ch. 24)

  • Hashimoto encephalopathy (see “Hashimoto Encephalopathy” below)

  • CNS vasculitis (see “Cerebral Vasculitis” in Ch. 19)

  • Demyelinating disease (see Ch. 21)

  • Neurosarcoidosis

• Malignancy

  • Multiple parenchymal metastases or leptomeningeal metastases (see “Brain Metastases” and “Leptomeningeal Metastases” in Chapter 24)

  • Frontal lobe tumor

  • Diffusely infiltrating tumor (e.g., gliomatosis cerebri; see “Gliomas” in Chapter 24)

  • Intravascular lymphoma (see “Intravascular Lymphoma” in Chapter 19)

• Chronic infections

  • AIDS (see “HIV Dementia and Hiv-Associated Neurocognitive Disorders” in Chapter 20)

  • Neurosyphilis

  • Toxins

  • Heavy metal poisoning

  • Chronic alcohol abuse

• Metabolic etiologies

  • Hepatic dysfunction

  • Chronic renal failure

  • Hyperammonemia (e.g., due to valproic acid or due to urea cycle disorder)

• Vascular etiologies:

  • Subclinical infarctions leading to accumulated burden of infarcted tissue as can occur in hypercoagulable states, CNS vasculitis, intravascular lymphoma, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (see Ch. 19)

• Adult-onset leukodystrophies (see Ch. 31)

• Atypically rapid courses of neurodegenerative diseases such as Alzheimer’s disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal syndrome

Many of these potential etiologies of rapidly progressive dementia can be discovered (or exonerated) by neuroimaging studies. A normal contrast-enhanced MRI requires extensive evaluation for potentially treatable systemic causes including complete metabolic panel, complete blood count, vitamin B12, HIV, rapid plasma reagin (RPR), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), autoimmune studies (antinuclear antibodies [ANA], anti-Ro, anti-La), paraneoplastic antibodies, and anti–thyroid peroxidase (anti-TPO) and antithyroglobulin (anti-TG) (for Hashimoto’s encephalopathy; see “Hashimoto’s Encephalopathy” below), as well as consideration of lumbar puncture to evaluate for inflammation, infection, and/or antibodies in the CSF. When MRI abnormalities are present but nonspecific (e.g., white matter lesions that could represent inflammatory disease versus neoplasm), brain biopsy may be necessary to make a diagnosis.

Creuztfeldt-Jakob Disease

Creuztfeldt-Jakob disease (CJD) is caused by accumulation of prions in the brain, leading to rapidly progressive dementia. Most cases are sporadic (sCJD) (i.e., no clear cause), although some cases are familial (familial CJD [fCJD], fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome), and some have been caused by consumption of infected beef (variant CJD [vCJD]) or by iatrogenic transmission (iCJD) from infected neurosurgical instruments, corneal transplants, and human pituitary hormones. The dementia in CJD can affect any/all cognitive domains and may begin with personality/psychiatric changes. Myoclonus (particularly startle-induced myoclonus) is common, but this finding may be absent in cases of CJD and is nonspecific since myoclonus can be seen in other etiologies of progressively altered cognition (e.g., renal failure, Alzheimer’s disease, corticobasal syndrome, or medication-induced encephalopathy; see “Myoclonus” in Ch. 23). Some cases of CJD begin with isolated visual symptoms (Heidenhain variant).

MRI is the most sensitive and specific test for sCJD (Vitali et al., 2011), demonstrating diffusion restriction in the cortical ribbon and basal ganglia (Fig. 22–6). (These findings are not seen in vCJD, which classically shows abnormalities in the pulvinar of the thalamus on FLAIR sequence.) The MRI features of CJD may not be present early in the disease, and may emerge only on subsequent repeat imaging as the disease progresses. Diffusion restriction in the cortical ribbon can also be seen in status epilepticus and hypoxic-ischemic injury, but both are usually easily distinguished from CJD by history. Limbic regions are rarely affected in isolation in CJD, and if signal changes isolated to limbic regions are seen on MRI in a patient with rapidly progressive dementia, the possibility of an autoimmune or paraneoplastic limbic encephalitis should be pursued (see “Autoimmune Limbic Encephalitis” in Ch. 24).

In sCJD, CSF 14-3-3 protein and periodic sharp-wave complexes on EEG may be present, but both sensitivity and specificity of these findings are much lower than the sensitivity and specificity of MRI, and the presence of CSF 14-3-3 and periodic sharp-wave complexes on EEG may vary over the course of the disease. Lumbar puncture should be considered to evaluate for alternative etiologies of rapidly progressive dementia (e.g., inflammatory CNS disease) if neuroimaging is not characteristic of CJD, but CSF studies cannot confirm or exclude a diagnosis of CJD.

Unfortunately, there is currently no effective treatment for CJD, so care is supportive. Patients generally do not survive for more than approximately 1 year from the time of diagnosis.

Hashimoto’s Encephalopathy

Hashimoto’s encephalopathy is an immune-mediated CNS disorder associated with anti-TPO and/or anti-TG antibodies that responds to immunmodulatory therapy. The condition is also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT). Despite the name and the association with anti–thyroid antibodies, there is no clear relationship to thyroid disease, and many patients with Hashimoto’s encephalopathy have normal thyroid function. The relationship between the disorder and the antibodies is unclear, especially since many elderly individuals may have elevated titers of these antibodies with no clinical correlate.

Hashimoto’s encephalopathy generally presents as a rapidly progressive dementia (over weeks to months). Some cases may present with stroke-like episodes without MRI evidence of stroke. Seizures and myoclonus can occur.

MRI is normal in most cases of Hashimoto’s encephalopathy, but may show nonspecific T2/FLAIR hyperintensities. CSF is inflammatory (elevated protein and lymphocytic pleocytosis) in most cases, although it can be normal. Inflammatory CSF in the setting of a rapid decline in cognition and a normal MRI can also occur in autoimmune or paraneoplastic limbic encephalitis (see “Autoimmune Limbic Encephalitis” in Ch. 24).

Many patients with Hashimoto’s encephalopathy demonstrate dramatic improvement with steroids. If there is a high index of suspicion for the disorder and no (or minimal) response to steroids, more aggressive immunomodulatory therapy can be considered and may lead to clinical improvement in some patients.